2.1. Introduction
Age-related macular degeneration (AMD) includes neovascular age-related macular degeneration (NVAMD), defined by pathological choroidal new vessels (CNV) under the macula. Neovascular age-related macular degeneration (NVAMD), defined by pathological choroidal new vessels (CNV) under the macula, is the leading cause of vision loss in in the elderly (see e.g., Congdon N, et al. (2004) Archives of ophthalmology; 122: 477-485; Green W R, Mol Vis 1999; 5:27).
NVAMD patients showed improved vision outcomes after intraocular injections of anti-vascular endothelial growth factor (VEGF). However, around 50% of treated patients manifest persistent plasma leakage, blood, lesion growth or progressive fibrosis, collectively called persistent disease activity (PDA) (Brown D M et al. (2006) The New England journal of medicine 355: 1432-1444; Heiser J S et al. (2012) Ophthalmology; Epub 2012/10/23; Rosenfield P J et al. (2006) The New England journal of medicine 355: 1419-1431; Martin D F et al. (2012) Ophthalmology 119: 1388-1398; Martin D F et al. (2011) The New England journal of medicine 364: 1897-1908). There are no treatments existing for PDA. Therefore, these patients are at risk for long-term vision loss (Rosenfeld P J et al. (2011) Ophthalmology 118: 523-530; Ying G-S et al. (2012) Invest Ophthalmol Vis Sci 53: 3681).
PDA occurs most frequently in NVAMD lesions with arteriolarization and perivascular fibrosis, a distinct pathology known as neovascular remodeling (NVR). Histopathology in surgically excised CNV of NVAMD patients demonstrate increased frequency of macrophages in association with NVR lesions (Tatar O et al. (2009) The British journal of ophthalmology 93: 159-165). In addition, systemic depletion of macrophages abrogates the NVR phenotype in mice resulting in smaller lesions (presumed capillaries) with less fibrosis (Espinosa-Heidmann D G et al. (2003) Invest Ophthalmol Vis Sci 44: 3586-3592). Thus, macrophages appear to promote NVR, and therapies directed against macrophages may be effective for the treatment of NVR in affected patients.
The intermediate kinase Calcium/Calmodulin-dependent Kinase Kinase 2 (CaMKK2) is a key regulatory kinase that has been shown to amplify macrophage effector function (Racioppi L et al. (2012) J Biol Chem 287: 11579-11591). CaMKK2 is activated within tumor-associated macrophages, and knockout of CaMKK2 attenuates macrophage-mediated tumor vascularization and growth. However, consistent with CaMKK2's role as an amplifier of effector function, mice null for CaMKK2 do not develop immunosuppression or susceptibility to infections. Thus, CaMKK2 appears to be a promising target for macrophage-mediated inflammation, including macrophage-mediated NVR in the setting of NVAMD and macrophage-mediated tumor growth in the setting of cancer.
In addition to this role in macrophage function, CaMKK2 is also expressed in areas of the brain that regulate satiety. As a result, there has been interest in identifying inhibitors of CaMKK2 (that cross the blood-brain barrier) as appetite-control drugs.